Abstract
Reversible acetylation of Tat is critical for its transactivation activity toward HIV-1 transcription. However, the enzymes involved in the acetylation/deacetylation cycles have not been fully characterized. In this study, by yeast two-hybrid assay, we have discovered the histone deacetylase HDAC6 to be a binding partner of Tat. Our data show that HDAC6 interacts with Tat in the cytoplasm in a microtubule-dependent manner. In addition, HDAC6 deacetylates Tat at Lys-28 and thereby suppresses Tat-mediated transactivation of the HIV-1 promoter. Inactivation of HDAC6 promotes the interaction of Tat with cyclin T1 and leads to an increase in Tat transactivation activity. These findings establish HDAC6 as a Tat deacetylase and support a model in which Lys-28 deacetylation decreases Tat transactivation activity through affecting the ability of Tat to form a ribonucleoprotein complex with cyclin T1 and the transactivation-responsive RNA.
Highlights
The transactivator protein Tat is essential for HIV-1 transcription
We further found that GFP-Tat interacted with endogenous HDAC6 in mammalian cells (Fig. 1D)
By GST pulldown assay, we further found that purified His-HDAC6 did not interact with purified GST
Summary
The transactivator protein Tat is essential for HIV-1 transcription. Tat enhances HIV-1 transcription elongation through binding to the transactivation-responsive RNA (TAR)2 structure, a stem-loop formed at the 5Ј-end of viral transcripts [1, 2]. Our data reveal that HDAC6 binds Tat and deacetylates Tat at Lys-28 in a microtubule-dependent manner and thereby regulates Tat transactivation activity. Yeast cells transformed with HDAC6 showed strong -galactosidase activity in a Tat-dependent pattern (Fig. 1A), indicating an interaction of HDAC6 with Tat in yeast.
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